Novel mutations and polymorphisms in the Fanconi anemia group C gene

Abstract

Fanconi anemia (FA) is an autosomal recessive disorder associated with hypersensitivity to DNA cross‐linking agents and bone marrow failure. At least four complementation groups have been defined, and the FA group C gene (FAC) has been cloned. We have screened 76 unrelated FA patients of diverse ethnic and geographic origins and from unknown complementation groups for mutations in the FAC gene either by chemical cleavage mismatch analysis or by single‐strand conformational polymorphism (SSCP). Five mutations were detected in four patients (5.3%), including two novel mutations (W22X and L496R). Nine polymorphisms were detected, seven of which have not been described previously (663A → G, L190F, IVS6 + 30C → T, 1312V, V449M, Q465R, and 1974G → A). Six of the nine polymorphisms occurred in patients or controls from the Tswana or Sotho chiefdoms of South Africa and were not found in 50 unrelated European controls. Restriction site assays were established for all 8 pathogenic mutations identified in the FAC gene to date and used to screen a total of 94 unrelated FA patients. This identified only one other group C patient, who was homozygous for the mutation IVS4 + 4A → T. This study indicates that the proportion of FA patients from complementation group C is generally likely to be less than 10%. Guidelines for the selection of FA patients for FAC mutation screening are proposed. © 1996 Wiley‐Liss, Inc.

Preimplantation HLA typing for stem cell transplantation treatment of congenital and acquired bone marrow failures

“…as mentioned, to avoid late complications due to severe GVH [3][4][5]. A total of 23 couples at risk for producing a progeny with FA presented for preimplantation HLA typing, including carriers of IVS 4+4 A-T mutation in FANCC gene, carriers of FANCD2, FANCF, FANCI, FAMCCJ, and FANCA gene mutations [22][23][24][25][26][27]. Overall, 63 cycles were performed, resulting in transfer of 61 unaffected HLA matched embryos in 41 cycles, yielding twelve unaffected pregnancies and birth of nine FA free and HLA matched children, as potential donors for their siblings.…”

Heterogeneous spectrum of mutations in the Fanconi anaemia group A gene

“…Almost all classes of mutations were observed, including a surprisingly high number of large intragenic deletions which removed one or more exons; these accounted for eight of the 31 mutations (26%) in this study (Table 1). No deletions of this sort have yet been observed in the FAC gene, 13,14 which suggests that there 15,28 The mutations are scattered throughout the coding sequence ( Figure 1), with no compelling evidence of mutation 'hotspots' at present. In this study, mutations were detected in 34 patients, which is 49% of the predicted number of FA-A cases which were screened.…”

“…[6][7][8] The group C gene was cloned by functional complementation, 9 and localised to chromosome 9q22.3. 6 Only 10 mutations have been detected in the FAC gene, [9][10][11][12][13][14][15] including one missense mutation of proven functional significance. 16 The group A gene (FAA), which accounts for 60-65% of FA in most populations, 17,18 was mapped to chromosome 16q24.3 by linkage analysis in FA-A families, 19 and subsequently identified by both functional complementation 20 and positional cloning.…”

Prompt and durable hematopoietic reconstitution by unrelated cord blood transplantation in a child with Fanconi anemia

“…Single-strand conformational polymorphism analysis was performed to screen the genomic DNA of the patient in exons and flanking intronic regions 1, 4 and 14 for the FA group C gene. [7][8][9] No mutation was detected in these 10 The main cause of the hemorrhage, however, was thought to be the thrombocytopenia. Bone marrow aspirate revealed the progression of dyserythropoietic features with less than 1% myeloblasts.…”